Brain injury continues to be a major cause of death and disability throughout the world. Our investigations of hyperbaric oxygen treatment (HBOT) indicate that it is a relatively safe treatment that has promise as a potential therapy for patients with severe traumatic brain injury (TBI). The goals of the present proposal are to further elucidate the mechanisms of action of HBOT on severe TBI and to test hypotheses that are crucial to the possible future design of a Phase III clinical trial. As consistently noted by the reviewers of our grant, our center and personnel are uniquely qualified to perform these goals. Our initial prospective clinical trial to assess the effectiveness of HBOT in severe TBI documented very significant improvement in survival, particularly in certain subgroups of patients. In our second study, HBOT was found to improve cerebral aerobic metabolism in patients with severe TBI, reduce elevated intracranial pressure, and had a persistent positive effect for at least six hours following the treatment. Our work suggests that HBOT allows the brain to utilize increased amounts of oxygen more efficiently following treatment. Recently, increasing the inspired oxygen concentration (FiO2) to 100% has been proposed as an alternative way of delivering supranormal levels of oxygen to severe TBI patients. Experimental investigation in a fluid percussion rat model using HBOT at 1.5 ATA (atmospheres absolute) for 60 minutes followed by 3 hours of 100% fraction of inspired oxygen (Fi02) have given optimum results in terms of mitochondrial functional and neurobehavioral improvement. The clinical and experimental data together provide a strong basis for the restorative effect of the combination of hyper- and normobaric hyperoxia on severe TBI. The goal of the present supplemental proposal is to evaluate in our ongoing prospective, randomized clinical trial the use HBOT and 100% FiO2 in combination. We are presently evaluating HBO for 60 minutes, 100% FiO2 for 3 hours, and standard therapy in a group of severely brain-injured patients. The fourth group will be 60 minutes of HBO followed by 3 hours of 100% FiO2. The study design would not change. Monitoring of the effect of oxygen treatment on cerebral metabolism and intracranial pressure, as well as potential oxygen toxicity to the brain and lungs, would be evaluated. [unreadable] [unreadable]